Strategy of targeting endogenous regulators has emerged to limit inflammation and preserve tissue homeostasis opening a new paradigm in the treatment of chronic infectious and inflammatory conditions including periodontal disease. Ubiquitination is a reversible post-translational modification that can terminate cell signaling through proteasome-mediated degradation and also involved in protein trafficking and activation of kinases and phosphatases thereby playing a key role in the regulation of multiple inflammatory signaling cascades. While ubiquitination is essential to activate immune responses, its tight regulation and timely termination is the key to keep the potentially damaging inflammatory signals in check and preserve tissue homeostasis. Therefore, ubiquitination and ubiquitin-related events are essential in the regulation of functional immune cell plasticity and homeostatic events. However, there are yet no studies which investigated their role on the oral mucosa. Recently, A20 (also known as TNF alpha induced protein 3 or TNFAip3) has emerged as a critical negative regulator of inflammation through interfering with ubiquitination. A20 lies downstream of Toll like receptors (TLRs), NOD-like receptors, T cell receptor, and cytokine receptors (e.g. TNFR, IL-1R, IL-17R) and regulates inflammation mainly by restricting NF-?B pathway and modulates other cellular functions such as apoptosis, necroptosis and autophagy. Through its function in a diverse set of biological mechanisms, A20 is implicated in gastrointestinal, cardiovascular, and pulmonary diseases, autoimmune and neurological disorders, rheumatoid arthritis, aging and mostly in cancer. Likewise, we now have evidence supporting the hypothesis that A20 is one of the key regulatory factors within the oral mucosa and acts as a gatekeeper to restrict periodontal inflammation through interfering with critical upstream and downstream events. The overall goal of the current proposal is to delineate the role of ubiquitination with specific focus being on the function and regulation of A20 in host-oral microbiome interactions as they relate to the key cellular and molecular pathways in the course of periodontitis. We seek to uncover a previously unexplored area within the oral cavity through conducting complementary experiments involving clinical studies and well characterized preclinical disease models. The proposed studies are expected to unveil novel biological and mechanistic insights and lead to new concepts and therapeutics not only for periodontal disease but also for other local infection driven inflammatory conditions as well as diseases associated with PD such as oral cavity malignancies and aging related conditions.